Danish Research Institute of Translational Neuroscience DANDRITE-Nordic EMBL Partnership for Molecular Medicine, and Center of Excellence PROMEMO, 8000 Aarhus C, Denmark; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Danish Research Institute of Translational Neuroscience DANDRITE-Nordic EMBL Partnership for Molecular Medicine, and Center of Excellence PROMEMO, 8000 Aarhus C, Denmark; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Cell Rep. 2023 Nov 28;42(11):113333. doi: 10.1016/j.celrep.2023.113333. Epub 2023 Oct 27.
Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neuromuscular junction morphology and fish motility. In mice, SorCS2 and PGRN are co-expressed by newborn MNs from embryonic day 9.5 until adulthood. Using cell-fate tracing and nerve segmentation, we find that SorCS2 deficiency perturbs cell-fate decisions of brachial MNs accompanied by innervation deficits of posterior nerves. Additionally, adult SorCS2 knockout mice display slower motor nerve regeneration. Interestingly, primitive macrophages express high levels of PGRN, and their interaction with SorCS2-positive motor axon is required during axon pathfinding. We further show that SorCS2 binds PGRN to control its secretion, signaling, and conversion into granulins. We propose that PGRN-SorCS2 signaling controls MN development and regeneration in vertebrates.
运动神经元（MN）的发育和神经再生需要大量分子的协调作用。在这里，我们鉴定出 SorCS2 是一种颗粒蛋白前体（PGRN）受体，它在斑马鱼和小鼠中对于 MN 的多样化和轴突生长是必需的。在斑马鱼中， SorCS2 的敲低也会影响神经肌肉接头的形态和鱼的运动能力。在小鼠中， SorCS2 和 PGRN 由从胚胎第 9.5 天到成年的新生 MN 共同表达。通过细胞谱系追踪和神经分割，我们发现 SorCS2 缺乏会干扰臂部 MN 的细胞命运决定，并伴有后神经的神经支配缺陷。此外，成年 SorCS2 敲除小鼠表现出较慢的运动神经再生。有趣的是，原始巨噬细胞表达高水平的 PGRN，并且它们与 SorCS2 阳性运动轴突的相互作用在轴突寻径过程中是必需的。我们进一步表明， SorCS2 结合 PGRN 以控制其分泌、信号传递和转化为颗粒素。我们提出 PGRN-SorCS2 信号控制脊椎动物 MN 的发育和再生。
